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Gordon McVie on ASCO10: Highlights & Assessment

CHICAGO—I've tried in this article to pull out of a meeting with 33,000 people and thousands of abstracts a few key points which are of interest to you oncologists who didn't make it, or those who came and didn't see everything—which means just about everybody!

Good News about Melanoma: Ipilimumab

Headlines immediately hit the papers about the news about melanoma—about ipilimumab, an antibody that works not against the melanoma cell or any epitope or genetic mutation therein, but against the molecules that suppress T-cells. I overheard someone call this meeting “the Melanoma ASCO” because, for the first time in the 40 years I've been practicing oncology, we've actually got a positive result in terms of survival in metastatic melanoma.

This is not only good news for patients with malignant melanoma but is also a vindication of those translational scientists who have been working in immunotherapy in melanoma for many years.

This is a drug that is unleashing the cytotoxic T-cells (CTLA-4) from whatever it is that is suppressing them, allowing them to reject cancer cells. So it is suppressing the suppressor, or taking the foot off the brake pedal which is dampening down the immunity associated with patients with melanoma.

A Phase III trial out of the Angeles Clinic and Research Institute in Santa Monica, California, showed ipilimumab to lengthen survival quite remarkably: Patients with advanced, previously treated melanoma who received the drug lived 34% longer than those who received the immune-stimulating gp100 peptide vaccine. Ipilimumab has already moved into first-line trials; these patients have had previous treatment for their melanoma but, as we know, most of those treatments don't work anyway so they're virtually as-new patients.

Ipilimumab is going to be a challenge to oncologists because it produces a really different kind of pattern of toxicity; some toxicities which you have rarely seen before in your practice, because it's dampening down the dampeners of immunity.

And it's allowing some patients to develop classic autoimmune diseases which are normally suppressed, of course: Diarrhea, Crohn's disease, ulcerative colitis have been found in a significant number of patients, sometimes quite serious and requiring aggressive steroid treatment. There have also been cases of autoimmune thyroiditis, not a common side effect of an anti-cancer drug, and most extraordinary of all, an autoimmune attack on the pituitary gland. This is difficult to diagnose if you're not expecting it and you're a general practitioner new to ipilimumab.

The recommendation from the experts who have been taking part in these trials is that the patient has to be instructed in more depth than normal on the possible side effects. The main message is that if you get into trouble, come back to the oncologist who will know that diarrhea means instigating immediate steroid treatment.

NSCLC: B-RAF Mutations, ALK

Last year's ASCO saw a bit of melanoma excitement with the B-RAF mutations being found to be present in broad numbers of melanomas, but also targetable. The studies from last year are continuing to look positive in the follow-up this year.

B-RAF mutations in lung cancer are also hitting the headlines because the same anti-cancer drugs targeting B-RAF mutations in melanoma are now being used to target the B-RAF mutations in lung cancer. Not a huge number of patients with non-small-cell lung cancer (NSCLC) have these mutations, but the anti-BRAF agents are showing good, consistent responses, and that's rather good news.

Quite interestingly, a completely new target for lung cancer is ALK, the anaplastic lymphoma kinase gene. It seems that around 5% of NSCLC patients have this ALK mutation. They tend to be patients with adenocarcinoma, either former smokers or non-smokers, and often women.

The good news is that for patients with the ALK mutation, even very early studies have shown remarkable responses, in some cases complete response. These are patients previously treated with chemotherapy for metastatic NSCLC, and we're looking at response rates above 60%, which is quite significant.

Ovarian Cancer: Bevacizumab Maintenance, PARP-1Inhibitors

In ovarian cancer there are two trials I thought noteworthy: The first was an improvement in rogression-free survival by the addition of bevacizumab in patients who had either partial or complete remission, from the classic upfront platinum-taxane combination.

A big Phase III trial lead by Dr. Robert Burger of Fox Chase Cancer Center has shown a four-month progression-free survival difference for those patients who receive maintenance bevacizumab rather than no adjuvant maintenance treatment.

This is important—it's not an overall survival difference, but a bigger study or longer follow-up might have shown that. So far it hasn't, but nevertheless this kind of survival gain has not been seen in previous trials for the last 10 years. Adding anti-angiogenesis agents upfront with the combination of platinum-taxane has previously not been particularly productive and has not improved either response rates or time to progression, but it seems that in this situation the anti-angiogenesis agent is beneficial given after tumor reduction by surgery or surgery and chemotherapy.

The second noteworthy trial in ovarian cancer was an early study of PARP-1 inhibitors. At the 2009 ASCO meeting, PARP-1 inhibitors were all over the place, with really exciting data in breast and ovarian patients who had BRCA1 and BRCA2 mutations. We know that one of the many functions of those genes is facilitating DNA repair, and that PARP-1 inhibitors are important in exploiting and aggravating genetic injury; really quite impressive response rates were seen in the early trials.

We had hoped that breast cancer patients with triple-negative disease might respond to PARP-1 inhibitors; there was a hint of some sort of activity. The hope was that the triple-negative patients would have BRCA-like phenotypes, but unfortunately the negative report from ASCO 2010 hits that on the head.

The PARP-1 inhibitors, or at least the one that was tested (there are about eight or nine of them), have so far not been substantially effective in triple-negative breast cancer patients. However the ovarian study was positive and much more promising. This was a study of ovarian cancer patients who are BRCA-wild type—over 90% of ovarian cancers—in other words, they do not have mutations in BRCA1 and BRCA2.

This is particularly promising because it could affect a lot more patients: There was evidence presented at this ASCO meeting that PARP-1 inhibitors can produce important clinical responses in those ovarian cancer patients with the BRCA wild type.

So independent of the BRCA status we're seeing responses. This is very good news because not a great deal has been happening to prolong the lives of ovarian cancer patients, who frequently present or are diagnosed all too late. So, two bits of hope there in maintenance treatment with bevacizumab and PARP-1 inhibitors, which hopefully will move up the rank into at least second-line and probably first-line treatment.

Prostate Cancer: Zoledronic Acid Upfront

In prostate cancer there was a lot of focus on the effect of zoledronic acid in upfront management, in the hope that skeletal-related events (SREs) will be reduced and their onset will be delayed. A randomized trial, presented by Dr Karim Fizazi of the Institut Gustave Roussy, Paris, has now compared an antibody that showed some promise last year in Phase II trials, denosumab, against zoledronic acid.

Both drugs delay the onset of skeletal problems but denosumab seems to have a slightly better performance so far. Both seem to give the unusual side effect of osteonecrosis of the jaw but in very small numbers, two or three percent, out of big studies which have been reported either here or in intermediate meetings since the 2009 ASCO meeting.

An important prostate cancer trial with UK involvement was reported by the Medical Research Council on behalf of the National Cancer Institute Canada and the South West Oncology Group: “An intergroup randomized phase III study of androgen deprivation therapy plus radiation therapy in locally advanced prostate cancer.”

This was a very important study because it was asking the question: How do we best use what we've got in the treatment of higher malignancy grades of prostate cancer? Do you treat prostate cancer patients with hormones only, or hormones plus radiotherapy for better control of local disease?

The answer, from one of the largest studies so far carried out, was that radiotherapy localized to the prostate does improve the outcome for patients with prostate cancer on top of hormone treatment. So we're saying that the new standard of care for prostate cancer should be hormone treatment and local radiation on top of that.

Some radiation therapists are shocked that this is not already adopted by all doctors, but the evidence base was thin. Not any longer!

Breast Cancer: Disappointments

This was not a year for reporting big studies in breast cancer; there were a number of disappointments, including negative data from sunitinib in combination with other drugs in breast cancer.

A new compound called eribulin, derived from a marine sponge, was found to increase overall survival by 2.5 months compared with the physician's treatment of choice, in heavily pretreated metastatic breast cancer.

The first mature report, looking at localized radiotherapy post-breast-conservation surgery vs six weeks of conventional external-beam radiation to the breast, emerged from the TARGIT trial, presented by Michael Baum of University College London.

There doesn't seem to be any difference in local control between the targeted radiotherapy vs the external- beam radiotherapy given over six weeks. This is good news as there is far less radiation-associated toxicity with locally targeted radiation therapy.

There needs to be several years follow-up, and it will be interesting to see how this study relates, as a multicenter study, to the ELectron IntraOperative Therapy (ELIOT) trial from my own institute (IEO) in Milan, where local radiotherapy is applied during the operation, so the patient wakes up having had surgery and radiotherapy.

This is a 1200-patient randomized trial from a single institute, and the last patient was randomized three years ago. Like TARGIT the standard comparator arm is six weeks of daily external-beam radiation.

Brain Cancer, Bladder Cancer

Not a lot of news to report in brain cancer, but a very important management study looking at elderly patients with brain cancer—do they really need six weeks of radiation therapy plus chemotherapy—for example, temozolomide?

The answer is: no, they don't. You can either give two weeks of radiotherapy or just temozolomide alone. In an elderly patient having to travel to hospital every day for six weeks, saving what might be a great deal of their remaining lifetime, this is an important health care delivery study.

In bladder cancer, one trial that caught my eye was in post-cystectomy patients—adjuvant chemotherapy, yes or no? Again, the first of its kind with a positive result for chemotherapy, post-cystectomy.

Amyloidosis

And then just to end, I'd like to draw attention to a very authoritative discussion of amyloidosis, an issue that crops up all over the oncology area and is generally thought to be a little bit outside the field, but it's not.

It was interesting to hear from Prof Giampaolo Merlini, of the University of Pavia, Italy, that there are now tests for early amyloidosis, particularly testing the urine of patients suspected of having a systemic disease.

There are also giveaway signs on cardiac ultrasounds and, if found early, amyloidosis is treatable and possibly curable. The management is bevacizumab, melphalan, and steroids such as dexamethasone and prednisone; the same sort of front-line cocktail that you would expect to give a patient with multiple myeloma. Amyloidosis is important to catch early and should be treated as if you were treating a myeloma patient.

Excellent Educational Sessions

This year also saw a number of high-quality educational sessions at the meeting, and it's good to see physicians picking up the latest practice and taking it home. There have also been a number of practice-changing Phase III trials in a number of different cancers; not a great deal of translational research, but more and more we look to the AACR for that.

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